Chlorpromazine

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Chlorpromazine
Skeletal formula of chlorpromazine
Ball-and-stick model of the chlorpromazine molecule
Clinical data
Trade names Largactil, Thorazine, others
AHFS/Drugs.com Monograph
MedlinePlus a682040
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration		 Oral (tablets and syrup available), rectal, IM, IV infusion
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 10–80% (Oral; large interindividual variation)[1]
Protein binding 90–99%[1]
Metabolism Liver, mostly CYP2D6-mediated[1]
Biological half-life 30 hours[2]
Excretion Urine (43–65% in 24 hrs)[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.000.042
Chemical and physical data
Formula C17H19ClN2S
Molar mass 318.86 g/mol (free base)
355.33 g/mol (hydrochloride)
3D model (Jmol)
  (verify)

Chlorpromazine (CPZ), marketed under the trade names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar disorder, attention deficit hyperactivity disorder, nausea and vomiting, anxiety before surgery, and hiccups that do not improve following other measures. It can be given by mouth, by injection into a muscle, or into a vein.[2]

Common side effects include movement problems, sleepiness, dry mouth, low blood pressure upon standing, and increased weight. Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, neuroleptic malignant syndrome, and low white blood cell levels. In older people with psychosis as a result of dementia it may increase the risk of dying. It is unclear if it is safe for use in pregnancy. Chlorpromazine is in the typical antipsychotic class. Its mechanism of action is not entirely clear but believed to be related to its ability as a dopamine antagonist. It also has anti-serotonergic and antihistaminergic properties.[2]

Chlorpromazine was discovered in 1950 and was the first antipsychotic.[3][4] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] Its introduction has been labeled as one of the great advances in the history of psychiatry.[6][7] It is available as a generic medication.[2] The wholesale cost in the developing world is between US$0.02 and US$0.12 per day.[8] In the United States it costs about US$2 per day.[2]

Medical uses[edit]

Chlorpromazine is classified as a low-potency typical antipsychotic and in the past was used in the treatment of both acute and chronic psychoses, including schizophrenia and the manic phase of bipolar disorder, as well as amphetamine-induced psychoses. Low-potency antipsychotics have more anticholinergic side effects, such as dry mouth, sedation, and constipation, and lower rates of extrapyramidal side effects, while high-potency antipsychotics (such as haloperidol) have the reverse profile.[9]

Chlorpromazine has also been used in porphyria and as part of tetanus treatment. It still is recommended for short-term management of severe anxiety and psychotic aggression. Resistant and severe hiccups, severe nausea/emesis, and preanesthetic conditioning are other uses.[9][10] Symptoms of delirium in medically-hospitalized AIDS patients have been effectively treated with low doses of chlorpromazine.[11]

Other[edit]

Chlorpromazine is occasionally used off-label for treatment of severe migraine.[12][13] It is often, particularly as palliation, used in small doses to reduce nausea suffered by opioid-treated cancer patients and to intensify and prolong the analgesia of the opioids as well.[12][14]

In Germany, chlorpromazine still carries label indications for insomnia, severe pruritus, and preanesthesia.[15]

Comparison of chlorpromazine to placebo[16]
Measured outcome Findings in words Findings in numbers Quality of evidence
Global effects
Not any improvement (9 weeks – 6 months) 30% less risk of having no improvement in mental state, behaviour and functioning RR 0.7 CI 0.6 to 0.9 Very low (estimate of effect uncertain)
Relapse (6 months – 2 years) 35% less risk of relapse RR 0.7 CI 0.5 to 0.9

Adverse effects[edit]

See also: List of adverse effects for chlorpromazine
"Thorazine shuffle" redirects here. For the Gov't Mule song, see Dose (album).

There appears to be a dose-dependent risk for seizures with chlorpromazine treatment.[17] Tardive dyskinesia and akathisia are less commonly seen with chlorpromazine than they are with high potency typical antipsychotics such as haloperidol[18] or trifluoperazine, and some evidence suggests that, with conservative dosing, the incidence of such effects for chlorpromazine may be comparable to that of newer agents such as risperidone or olanzapine.[19]

Chlorpromazine may deposit in ocular tissues when taken in high dosages for long periods of time.

Comparison of chlorpromazine to placebo[16]
Measured outcome Findings in words Findings in numbers Quality of evidence
Adverse effects
Weight gain 5 times more likely to have considerable weight gain, around 40% with chlorpromazine gaining weight RR 4.9 CI 2.3 to 10.4 Very low (estimate of effect uncertain)
Sedation 3 times more likely to cause sedation, around 30% with chlorpromazine RR 2.8 CI 2.3 to 3.5
Acute movement disorder 3.5 times more likely to cause easily reversible but unpleasant severe stiffening of muscles, around 6% with chlorpromazine RR 3.5 CI 1.5 to 8.0
Parkinsonism 2 times more likely to cause parkinsonism (symptoms such as tremor, hesitancy of movement, decreased facial expression), around 17% with chlorpromazine RR 2.1 CI 1.6 to 2.8
Decreased blood pressure with dizziness 3 times more likely to cause decreased blood pressure and dizziness, around 15% with chlorpromazine RR 2.4 CI 1.7 to 3.3

Contraindications[edit]

Absolute contraindications include:[1]

  • Previous hypersensitivity (including jaundice, agranulocytosis, etc.) to phenothiazines, especially chlorpromazine, or any of the excipients in the formulation being used.

Relative contraindications include:[1]

Very rarely, elongation of the QT interval may occur, increasing the risk of potentially fatal arrhythmias.[20]

Interactions[edit]

Consuming food prior to taking chlorpromazine orally limits its absorption, likewise cotreatment with benztropine can also reduce chlorpromazine absorption.[1] Alcohol can also reduce chlorpromazine absorption.[1] Antacids slow chlorpromazine absorption.[1] Lithium and chronic treatment with barbiturates can increase chlorpromazine clearance significantly.[1] Tricyclic antidepressants (TCAs) can decrease chlorpromazine clearance and hence increase chlorpromazine exposure.[1] Cotreatment with CYP1A2 inhibitors like ciprofloxacin, fluvoxamine or vemurafenib can reduce chlorpromazine clearance and hence increase exposure and potentially also adverse effects.[1] Chlorpromazine can also potentiate the CNS depressant effects of drugs like barbiturates, benzodiazepines, opioids, lithium and anaesthetics and hence increase the potential for adverse effects such as respiratory depression and sedation.[1]

It is also a moderate inhibitor of CYP2D6 and also a substrate for CYP2D6 and hence can inhibit its own metabolism.[9] It can also inhibit the clearance of CYP2D6 substrates such as dextromethorphan and hence also potentiate their effects.[9] Other drugs like codeine and tamoxifen which require CYP2D6-mediated activation into their respective active metabolites may have their therapeutic effects attenuated.[9] Likewise CYP2D6 inhibitors such as paroxetine or fluoxetine can reduce chlorpromazine clearance and hence increase serum levels of chlorpromazine and hence potentially also its adverse effects.[1] Chlorpromazine also reduces phenytoin levels and increases valproic acid levels.[1] It also reduces propranolol clearance and antagonises the therapeutic effects of antidiabetic agents, levodopa (a Parkinson's medication. This is likely due to the fact that chlorpromazine antagonises the D2 receptor which is one of the receptors dopamine, a levodopa metabolite, activates), amfetamines and anticoagulants.[1] It may also interact with anticholinergic drugs such as orphenadrine to produce hypoglycaemia (low blood sugar).[1]

Chlorpromazine may also interact with epinephrine (adrenaline) to produce a paradoxical fall in blood pressure.[1] Monoamine oxidase inhibitors (MAOIs) and thiazide diuretics may also accentuate the orthostatic hypotension experienced by those receiving chlorpromazine treatment.[1] Quinidine may interact with chlorpromazine to increase myocardialdepression.[1] Likewise it may also antagonize the effects of clonidine and guanethidine.[1] It also may reduce the seizure threshold and hence a corresponding titration of anticonvulsant treatments should be considered.[1] Prochlorperazine and desferrioxamine may also interact with chlorpromazine to produce transient metabolic encephalopathy.[1]

Other drugs that prolong the QT interval such as quinidine, verapamil, amiodarone, sotalol and methadone may also interact with chlorpromazine to produce additive QT interval prolongation.[1]

Tolerance and withdrawal[edit]

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[21] While withdrawal symptoms can occur, there is no evidence that tolerance develops to the drug's antipsychotic effects. A patient can be maintained for years on a therapeutically effective dose without any decrease in effectiveness being reported. Tolerance appears to develop to the sedating effects of chlorpromazine when it is first administered. Tolerance also appears to develop to the extrapyramidal, parkinsonian and other neuroleptic effects, although this is debatable.[22]

A failure to notice withdrawal symptoms may be due to the relatively long half life of the drug resulting in the extremely slow excretion from the body. However, there are reports of muscular discomfort, exaggeration of psychotic symptoms and movement disorders, and difficulty sleeping when the antipsychotic drug is suddenly withdrawn, but after years of normal doses these effects are not normally seen.[22]

Pharmacology[edit]

Pharmacokinetics[edit]

Pharmacokinetic parameters of chlorpromazine[1][9][23]
Bioavailability tmax CSS Protein bound Vd t1/2 Details of metabolism Excretion Notes
10–80% 1–4 hours (Oral); 6–24 hours (IM) 100–300 ng/mL 90–99% 10–35 L/kg (mean: 22 L/kg) 30±7 hours CYP2D6, CYP1A2—mediated into over 10 major metabolites.[9] The major routes of metabolism include hydroxylation, N-oxidation, sulphoxidation, demethylation, deamination and conjugation. There is little evidence supporting the development of metabolic tolerance or an increase in the metabolism of chlorpromazine due to microsomal liver enzymes following multiple doses of the drug.[24] Urine (43–65% after 24 hours) Its high degree of lipophilicity (fat solubility) allows it to be detected in the urine for up to 18 months.[1][25] Less than 1% of the unchanged drug is excreted via the kidneys in the urine, in which 20–70% is excreted as conjugated or unconjugated metabolites, whereas 5–6% is excreted in feces.[25]
Three common metabolites of chlorpromazine

Pharmacodynamics[edit]

Chlorpromazine is a very effective antagonist of D2 dopamine receptors and similar receptors, such as D3 and D5. Unlike most other drugs of this genre, it also has a high affinity for D1 receptors. Blocking these receptors causes diminished neurotransmitter binding in the forebrain, resulting in many different effects. Dopamine, unable to bind with a receptor, causes a feedback loop that causes dopaminergic neurons to release more dopamine. Therefore, upon first taking the drug, patients will experience an increase in dopaminergic neural activity. Eventually, dopamine production of the neurons will drop substantially and dopamine will be removed from the synaptic cleft. At this point, neural activity decreases greatly; the continual blockade of receptors only compounds this effect.[9]

Chlorpromazine acts as an antagonist (blocking agent) on different postsynaptic and presynaptic receptors:

  • Dopamine receptors (subtypes D1, D2, D3 and D4), which account for its different antipsychotic properties on productive and unproductive symptoms, in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extrapyramidal effects
  • Serotonin receptors (5-HT1 and 5-HT2), with anxiolytic, and antiaggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain and ejaculation difficulties.
  • Histamine receptors (H1 receptors, accounting for sedation, antiemetic effect, vertigo, and weight gain)
  • α1- and α2-adrenergic receptors (accounting for sympatholytic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism—controversial. Also associated with weight gain as a result of blockage of the adrenergic alpha 1 receptor)
  • M1 and M2 muscarinic acetylcholine receptors (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, sinus tachycardia, electrocardiographic changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects).

The presumed effectiveness of the antipsychotic drugs relied on their ability to block dopamine receptors. This assumption arose from the dopamine hypothesis that maintains that both schizophrenia and bipolar disorder are a result of excessive dopamine activity. Furthermore, psychomotor stimulants like cocaine that increase dopamine levels can cause psychotic symptoms if taken in excess.[26]

Chlorpromazine and other typical antipsychotics are primarily blockers of D2 receptors. In fact an almost perfect correlation exists between the therapeutic dose of a typical antipsychotic and the drug's affinity for the D2 receptor. Therefore, a larger dose is required if the drug’s affinity for the D2 receptor is relatively weak. A correlation exists between average clinical potency and affinity of the antipsychotics for dopamine receptors.[22] Chlorpromazine tends to have greater effect at serotonin receptors than at D2 receptors, which is notably the opposite effect of the other typical antipsychotics. Therefore, chlorpromazine with respect to its effects on dopamine and serotonin receptors is more similar to the atypical antipsychotics than to the typical antipsychotics.[22]

Chlorpromazine and other antipsychotics with sedative properties such as promazine and thioridazine are among the most potent agents at α-adrenergic receptors. Furthermore, they are also among the most potent antipsychotics at histamine H1 receptors. This finding is in agreement with the pharmaceutical development of chlorpromazine and other antipsychotics as anti-histamine agents. Furthermore, the brain has a higher density of histamine H1 receptors than any body organ examined which may account for why chlorpromazine and other phenothiazine antipsychotics are as potent at these sites as the most potent classical antihistamines.[27]

In addition to influencing the neurotransmitters dopamine, serotonin, epinephrine, norepinephrine, and acetylcholine it has been reported that antipsychotic drugs could achieve glutamanergic effects. This mechanism involves direct effects on antipsychotic drugs on glutamate receptors. By using the technique of functional neurochemical assay chlorpromazine and phenothiazine derivatives have been shown to have inhibitory effects on NMDA receptors that appeared to be mediated by action at the Zn site. It was found that there is an increase of NMDA activity at low concentrations and suppression at high concentrations of the drug. No significant difference in glutamate and glycine activity from the effects of chlorpromazine were reported. Further work will be necessary to determine if the influence in NMDA receptors by antipsychotic drugs contributes to their effectiveness.[28]

Chlorpromazine does also act as FIASMA (functional inhibitor of acid sphingomyelinase).[29]

Peripheral effects[edit]

Chlorpromazine is an antagonist to H1 receptors (provoking antiallergic effects), H2 receptors (reduction of forming of gastric juice), M1 and M2 receptors (dry mouth, reduction in forming of gastric juice) and some 5-HT receptors (different anti-allergic/gastrointestinal actions).

Because it acts on so many receptors, chlorpromazine is often referred to as a "dirty drug".[30]

History[edit]

Advertisement for Thorazine (chlorpromazine) from the early 1960s[31]

In 1933, the French pharmaceutical company Laboratoires Rhône-Poulenc began to search for new anti-histamines. In 1947, it synthesized promethazine, a phenothiazine derivative, which was found to have more pronounced sedative and antihistaminic effects than earlier drugs.[32] A year later, the French surgeon Pierre Huguenard used promethazine together with pethidine as part of a cocktail to induce relaxation and indifference in surgical patients. Another surgeon, Henri Laborit, believed the compound stabilized the central nervous system by causing "artificial hibernation", and described this state as "sedation without narcosis". He suggested to Rhône-Poulenc that they develop a compound with better stabilizing properties.[33] In December 1950, the chemist Paul Charpentier produced a series of compounds that included RP4560 or chlorpromazine.[3] Simone Courvoisier conducted behavioural tests and found chlorpromazine produced indifference to aversive stimuli in rats. Chlorpromazine was distributed for testing to physicians between April and August 1951. Laborit trialled the medicine on at the Val-de-Grâce military hospital in Paris, using it as an anaesthetic booster in intravenous doses of 50 to 100 mg on surgery patients and confirming it as the best drug to date in calming and reducing shock, with patients reporting improved well being afterwards. He also noted its hypothermic effect and suggested it may induce artificial hibernation. Laborit thought this would allow the body to better tolerate major surgery by reducing shock, a novel idea at the time. Known colloquially as "Laborit's drug", chlorpromazine was released onto the market in 1953 by Rhône-Poulenc and given the trade name Largactil, derived from large "broad" and acti* "activity.[3]

Following on, Laborit considered whether chlorpromazine may have a role in managing patients with severe burns, Raynaud's phenomenon, or psychiatric disorders. At the Villejuif Mental Hospital in November 1951, he and Montassut administered an intravenous dose to psychiatrist Cornelia Quarti who was acting as a volunteer. Quarti noted the indifference, but fainted upon getting up to go to the toilet, and so further testing was discontinued (orthostatic hypotension is a possible side effect of chlorpromazine). Despite this, Laborit continued to push for testing in psychiatric patients during early 1952. Psychiatrists were reluctant initially, but on January 19, 1952, it was administered (alongside pethidine, pentothal and ECT) to Jacques Lh. a 24-year-old manic patient, who responded dramatically, and was discharged after three weeks having received 855 mg of the drug in total.[3]

Pierre Deniker had heard about Laborit's work from his brother-in-law, who was a surgeon, and ordered chlorpromazine for a clinical trial at the Hôpital Sainte-Anne in Paris where he was Men's Service Chief.[3] Together with the Director of the hospital, Professor Jean Delay, they published their first clinical trial in 1952, in which they treated 38 psychotic patients with daily injections of chlorpromazine without the use of other sedating agents.[34] The response was dramatic; treatment with chlorpromazine went beyond simple sedation with patients showing improvements in thinking and emotional behaviour.[35] They also found that doses higher than those used by Laborit were required, giving patients 75–100 mg daily.[3]

Deniker then visited America, where the publication of their work alerted the American psychiatric community that the new treatment might represent a real breakthrough. Heinz Lehmann of the Verdun Protestant Hospital in Montreal trialled it in 70 patients and also noted its striking effects, with patients' symptoms resolving after many years of unrelenting psychosis.[citation needed] By 1954, chlorpromazine was being used in the United States to treat schizophrenia, mania, psychomotor excitement, and other psychotic disorders.[9][36][37] Rhône-Poulenc licensed chlorpromazine to Smith Kline & French (today's GlaxoSmithKline) in 1953. In 1955 it was approved in the United States for the treatment of emesis (vomiting). The effect of this drug in emptying psychiatric hospitals has been compared to that of penicillin and infectious diseases.[34] But the popularity of the drug fell from the late 1960s as newer drugs came on the scene. From chlorpromazine a number of other similar antipsychotics were developed. It also led to the discovery of antidepressants.[38]

Chlorpromazine largely replaced electroconvulsive therapy, hydrotherapy,[39] psychosurgery, and insulin shock therapy.[35] By 1964, about 50 million people worldwide had taken it.[40] Chlorpromazine, in widespread use for 50 years, remains a "benchmark" drug in the treatment of schizophrenia, an effective drug although not a perfect one.[16] The relative strengths or potencies of other antipsychotics are often ranked or measured against chlorpromazine in aliquots of 100 mg, termed chlorpromazine equivalents or CPZE.[41]

Brand names[edit]

Brand names include Thorazine, Largactil, Hibernal, and Megaphen (sold by Bayer in West-Germany since July 1953[42]).

Veterinary use[edit]

The veterinary use of chlorpromazine has generally been superseded by use of acepromazine.[43]

Chlorpromazine may be used as an antiemetic in dogs and cats, or, less often, as sedative prior to anesthesia.[44] In horses, it often causes ataxia and altered mentation, and is therefore seldom used.[43][44]

It is commonly used to decrease nausea in animals that are too young for other common anti-emetics.[citation needed] It is also sometimes used as a preanesthetic and muscle relaxant in cattle, swine, sheep, and goats.[citation needed]

The use of chlorpromazine in food-producing animals is not permitted in the EU, as a maximum residue limit could not be determined following assessment by the European Medicines Agency.[45]

Research[edit]

Chlorpromazine has been studied in Naegleria fowleri infections in animal models.[46]

References[edit]

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  45. ^ "Chlorpromazine: summary report" (PDF). European Medicines Agency. Committee for Veterinary Medicinal Products. June 1996. Retrieved 2017-01-17. 
  46. ^ Kim, JH; Jung, SY; Lee, YJ; Song, KJ; Kwon, D; Kim, K; Park, S; Im, KI; Shin, HJ (November 2008). "Effect of therapeutic chemical agents in vitro and on experimental meningoencephalitis due to Naegleria fowleri" (PDF). Antimicrobial Agents and Chemotherapy. 52 (11): 4010–4016. doi:10.1128/AAC.00197-08. PMC 2573150Freely accessible. PMID 18765686. 

External links[edit]

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